Myelin deficiency in central nervous system occurs in genetic disease phenylketonuria (PKU). The primary aim of this research project is to provide an understanding of how the formation of myelin is impaired in animal models of PKU and to define the relationship between myelin and EEG abnormality. In earlier studies hypomyelination was induced by administration of either phenylalanine (phe) alone or p-chlorophenylalanine (pcpa) plus phe to immature rats. The two methods of simulating PKU are complicated by the facts that treatment with phe alone causes an increase in blood and brain levels of tryrosine, and pcpa plus phe treatment has other deleterious effects which are not associated with genetic PKU. A method of inducing PKU by treatment with alpha-methylphenylalanine (alpha-mpa) plus phe, does not suffer from the above drawbacks. We therefore investigated the effects of alpha-mpa plus phe treatment to rats on brain development. The result show that the myelin content of the brain is reduced by alpha-mpa plus phe treatment. It has been shown that treatment with steroid hormones enhance myelination. We will determine if treatment with hydrocortisone will overcome the myelin deficiency in animal models of PKU. We also plan to identify the reactions of lipid metabolism (specifically galactolipids and inositol phosphatides) which are affected in experimental PKU and to investigate the mechanisms of inhibition. The value of the auditory evoked response latencies in assessing the functional state of the central nervous system has been well documented. To relate abnormalities in EEG with myelin deficiency, we investigated the latencies of brainstem auditory evoked potentials (BAEP) in myelin deficiency induced by experimental hyperphenylalaninemia in immature rats, and by intoxication with triethyltin in young adult rats. Results of both experiments showed inverse correlation between myelin content and the BAEP latencies. We plan to compare BAEP latencies in myelin deficient mutant (quaking) mice and their littermate controls.